Progressive coccidioidomycosis is commonly associated with depressed or nondemonstrable cell-mediated immune response to Coccidioides immitis-derived antigens. We have performed studies to assess the basis of depressed T-cell reactivity by comparing the induction and expression of delayed-type hypersensitivity to coccidioidin in two mouse strains which differ in their susceptibility to infection with C. immitis. Intravenous injection of the highly susceptible BALB/c mouse strain with coccidioidal antigen or infection with arthroconidia via a pulmonary route suppressed delayed-type hypersensitivity response to coccidioidin. The suppression was mediated by an adherent splenic suppressor cell which, when adoptively transferred to syngeneic recipients, suppressed the efferent limb of the immune response. In contrast, spleen cells from antigen-treated or infected DBA/2 mice, which are relatively resistant to C. immitis, did not transfer suppressor activity. These collective results provide evidence that the activation of a splenic suppressor cell is associated with, and may contribute to, genetically-determined susceptibility to C. immitis. During the course of studies on antigen-induced suppression, we observed that BALB/c or DBA/2 mice injected intravenously with high doses of coccidioidal antigen manifest an immediate and lethal shock-like syndrome. This pathophysiologic response resembled the septic shock mediated by tumor necrosis factor-alpha (TNF-a), suggesting that C. immitis might induce this immunoinflammatory cytokine. Support for this interpretation was obtained by showing that peritoneal-exudate cells from BALB/c and DBA/2 mice se- creted substantial amounts of TNF-a when stimulated with C. immitis spherules. Induction of TNF-a by C. immitis is a new and important finding and merits investigation to delineate the role of this cytokine in host response to the fungus. Three specific aims are defined: (i) to confirm that the acute shock-like syndrome induced intravenous injection of BALB/c and DBA/2 mice with spherules is attributed to the production of TNF-a; (ii) to assess and compare the induction and expression of TNF-a throughout the course of active coccidioidomycosis in BALB/c and DBA/2 mice; and (iii) to evaluate the augmentation of antifungal activity by polymorphonuclear leukocytes and macrophages in response to recombinant TNF-a, alone and in synergy with interferon-gamma and granulocyte-macrophage colony stimulating factor.